Devices and methods for reducing intrathoracic pressure

ABSTRACT

Devices and methods are provided to treat acute and chronic heart failure by using one or more implantable or non-implantable sensors along with phrenic nerve stimulation to reduce intrathoracic pressure and thereby reduce pulmonary artery, atrial, and ventricular pressures leading to reduced complications and hospitalization.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/424,253 filed Feb. 3, 2017 (now U.S. Pat. No. 10,857,363), which is acontinuation of International Application No. PCT/US2015/047042 filedAug. 26, 2015, which claims the benefit of priority to U.S. ProvisionalApplication No. 62/041,987 filed Aug. 26, 2014, the contents of each ofwhich are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to treating heart failure (or dysfunction)and other cardiovascular disorders. In particular, the present inventionrelates to treating heart failure using one or more implantable ornon-implantable sensors along with phrenic nerve stimulation to reduceintrathoracic pressure and thereby reduce pulmonary artery, atrial,renal, and ventricular pressures leading to reduced complications andhospitalization. The present invention targets treating acutedecompensated heart failure (ADHF) utilizing a temporary or removablecatheter or electrode as well as a fully chronic implantable device forlong-term treatment of heart failure and pulmonary hypertensionpatients.

BACKGROUND OF THE INVENTION

Heart failure is a complex disease with many forms and causes. Ingeneral heart failure is defined as a condition where the cardiac outputis not adequate to meet the metabolic needs of the body, either at restor with exercise. Heart failure may be preceded by heart dysfunction,including, but not limited to ventricular dysfunction.

There are two forms of heart failure, one where the hearts ability toexpel the blood is impaired (systolic heart failure), another wherethere is a defect in ventricular filling (diastolic heart failure). Eachcan occur in isolation or together.

Current treatments for heart failure are available to slow the progressof the disease but do not cure the disease. Despite all the currenttherapeutic options, studies show that more than half of heart failurepatients die within 5 years of their diagnosis.

Accordingly it would be desirable to provide new and useful treatmentsfor heart failure or other cardiac/cardiovascular disease.

Pacemakers have been useful where there are cardiac bradyarrhythmias.Defibrillators are primarily used to prevent sudden cardiac death andtherefore have not improved the status of heart failure patients norhave they improved quality of life. Cardiac Resychronization Therapydevices (CRTs) have been useful or in patients with significantinterventricular delay or in preventing cardiac tachyarrhythmias orsudden cardiac death (CRT-Ds). There are many heart failure patients whomay not substantially benefit from one or more of these treatments ormay not have an improved quality of life from such treatments. Forexample, CRTs have not been approved for patients with ejectionsfractions greater than 35% and thus are not available for diastolicheart failure patients who typically have ejection fractions greaterthan 50%, or for systolic patients with an ejection fraction greaterthan 35%. Some studies show diastolic heart failure to account for up to⅓ of the patients presenting with heart failure. In addition, becausethe current treatments do not cure heart failure, additional treatmentthat may be used in combination with existing treatment may bebeneficial to the patients. Other devices such as temporary or chronicimplants stimulate the vagal nerve or cardiac plexus nerves to reducethe heart rate and/or improve cardiac contractility and achieve improvedcardiac output.

Many of the drugs such as calcium channel blockers, beta blockers, ACEinhibitors, diuretics, nitrates have had varying degrees of effect ondifferent manifestations of heart failure. However, not all are usefulto treat all heart failure patients. Furthermore, due to side effectssome patients withdraw from treatment. Pharmacological therapeuticapproaches to diastolic heart failure currently recommend diuretics andnitrates while the efficacy is uncertain for all diastolic heart failurepatients with calcium channel blockers, beta blockers, ACE inhibitors.Inotropic agents are not recommended for diastolic patients. Accordinglyit would be desirable to provide treatment for heart failure that may beused alone or in combination with other heart failure treatments. Itwould also be desirable to provide alternative or supplementarytreatment for diastolic heart failure patients.

Another cardiovascular condition that may exist with or without heartfailure is hypertension. Hypertension is believed to worsen heartfailure. It is also believed that hypertension may lead to diastolicheart failure. Studies have shown that treatment of hypertension reducesthe incidence of heart failure by 30% to 50%. Accordingly it would bedesirable to provide a treatment for hypertension.

In addition, a large percentage of heart failure patients also sufferfrom one or more forms of sleep apnea: obstructive sleep apnea orcentral sleep apnea, (each of which have significant clinicaldifferences), or mixed apneas. These conditions are believed to worsenprogression of heart failure. Obstructive sleep apnea is also believedto contribute to the development of heart failure, particularly throughhypertension.

Oxygen desaturations at night, changes in intrathoracic pressure, andarousals may adversely affect cardiac function and eventually result inan imbalance between myocardial oxygen delivery and consumption. Inheart failure patients with sleep apnea, there is believed to be anincreased incidence of atrial fibrillation, ventricular arrhythmias andlow left ventricular ejection fraction. Atrial fibrillation may becaused in part by increased right heart afterload due to hypoxicvasoconstriction which produces pulmonary hypertension. Periodicbreathing such as Cheyne-Stokes associated with CSA, create widefluctuations in intrathoracic pressure with a negative cardiovascularimpact. Central sleep apnea sometimes goes undiagnosed in heart failurepatients. The untreated central sleep apnea may trigger a negative chainof events that leads to worsening of heart failure.

Obstructive sleep apnea is believed to elicit a series of mechanical,hemodynamic, chemical, neural and inflammatory responses with adverseconsequences for the cardiovascular system for example, as described inSleep Apnea and Heart Failure Part I: Obstructive Sleep Apnea. Bradley,Douglas T, M D, Floras, John S., M D D Phil, Circulation Apr. 1, 2003.Many of these effects are believed to exacerbate conditions of heartfailure. Among these responses, increases in blood pressure as well asincreases in sympathetic activity are associated with obstructiveapneas. Obstructive sleep apnea also causes significant changes inintrathoracic pressure during apneic episodes applying further pressureon the heart.

Accordingly it would be desirable to treat sleep apnea in heart failureto reduce the negative effects of the apnea on the patient's diseasestatus.

CPAP is the most common treatment for obstructive sleep apnea and hasbeen proposed for central sleep apnea. CPAP requires an external deviceand patient compliance. In addition, its cardiovascular effects arecurrently unclear and some researchers believe that it can exacerbateheart failure in some patients, particularly where positive forcedpressure has a negative effect on a heart failure patient, such as, forexample, in patients where a reduced ventricular filling wouldsignificantly reduce cardiac output. Diaphragm stimulation has beenproposed to treat central sleep apnea by stimulating when apnea hasoccurred. However, the stimulation is provided after the apnea event hasoccurred rather than preventing the apnea event. Hypoglossal nervestimulation has been proposed to treat obstructive sleep apnea byincreasing patency in the upper airway to allow respiration.

It would accordingly be desirable to provide a treatment for sleep apneathat has a symbiotic therapeutic effect in treating heart failure orother cardiac/cardiovascular disease.

It would further be desirable to provide a treatment for heart failurepatients with sleep apnea that provides a separate or additionalfunction of treating heart failure.

Research has shown that voluntary control of breathing can improvecardiac disease, including hypertension and heart failure. It isbelieved that the reason for this is a biofeedback that exists betweenthe cardiac and respiratory systems due to baroreceptor based reflexes,and also a common central nervous control. Biofeedback systems forbreathing control have been provided. However, they require patientcompliance and diligence. Furthermore, because they require patientcompliance, the therapy can only occur during waking hours.

Heart failure is a chronic condition which leads to a reduction incardiac output and an increase in pulmonary pressures which in turnleads to pulmonary congestion and hospitalization. Yet various studieshave shown significant increases in stroke volume and cardiac output,particularly in patients who have undergone a CABG procedure, whennegative extrathoracic pressure is reduced. For example, results may beseen in further detail in the following:

-   Parker, J. et al, “Reducing Cardiac Filling Pressure Lowers    Norepinephrine Spillover in Patients With Chronic Hear Failure”,    Circulation, 2000; 101:2053-2059.-   CHATURVEDI, R. et al., “Use of Negative Extrathoracic Pressure to    Improve Hemodynamics After Cardiac Surgery”, The Annals of Thoracic    Surgery, 2008; 85, pp. 1355-1360, 2008.-   GOTTLIEB, J. et al., “Hypoxia, Not the Frequency of Sleep Apnea,    Induces Acute Hemodynamic Stress in Patients With Chronic Heart    Failure”, Journal of the American College of Cardiology, Vol. 54,    No. 18, pp. 1706-1712, Oct. 27, 2009.-   MERCHANT, F. et al., “Implantable Sensors for Heart Failure”,    Circulation: Arrhythmia and Electrophysiology, 2010; 3, pp. 657-667,    2010.-   BOCCHIARDO, M. et al., “Intracardiac impedance monitors stroke    volume in resynchronization therapy patients”, Europace: Journal of    the European Heart Rhythm Association, (2010) 12, pp. 702-707, Feb.    25, 2010.-   KASZALA, K. et al., “Device Sensing: Sensors and Algorithms for    Pacemakers and Implantable Cardioverter Defibrillators”,    Circulation, Journal of the American Heart Association, 2010; 122,    pp. 1328-1340, Sep. 28, 2010.-   LAU, C. et al., “Optimizing heart failure therapy with implantable    sensors”, Journal of Arrhythmia, 28(2012), pp. 4-18, Mar. 9, 2012.

Each of these references is incorporated herein by reference in itsentirety and for any purpose.

Previous attempts have been made to utilize an implantable medicaldevice to stimulate a patient's diaphragm to affect cardiac output. Forinstance, U.S. Pat. No. 7,277,757 to Casavant et al. discloses animplantable medical device that stimulates a nerve, such as a phrenicnerve, associated with respiration to cause a diaphragm of a patient tocontract. The implantable medical device receives a signal (e.g.,detecting a ventricular tachyarrhythmia, sensing a pressure thatindicates a need for increased cardiac output, or receiving a signalfrom a patient via a patient activator) that indicates a need forincreased cardiac output and stimulates the nerve in response to thesignal. Stimulation of the nerve may increase cardiac output of abeating or defibrillating heart.

However, Casavant et al. fails to disclosure pressure sensing andcreating lung volume with a reduction in intrathoracic pressure.Moreover, Casavant synchronizes its stimulation to the pacing of theheart and increases the amplitude of at least some of the pacing pulsesrather than providing for a sustainable stimulation over a continuousperiod of time.

SUMMARY OF THE INVENTION

In accordance with the invention, stimulation is provided to thediaphragm or phrenic nerve to elicit a diaphragm response to therebyprovide a therapeutic effect for a heart failure or other cardiac orcardiovascular patient.

In accordance with one aspect of the invention, stimulation to elicit adiaphragm response is provided to increase or normalize lung volume andin particular to increase functional residual capacity. It is believedthat stimulation to increase or to normalize lung volume or functionalresidual capacity may have one or more effects that may be therapeuticto cardiovascular or heart failure patients. Normalizing herein mayinclude for example, bringing a physiological parameter into a normal orhealthy region for patients or for a particular patient, or to a levelappropriate for a condition or state of a patient.

In accordance with another aspect of the invention stimulation isprovided to control breathing to reduce respiration rate and therebyreduce hypertension, reduce sympathetic nerve bias, and/or provideimproved blood gas levels.

In accordance with another aspect of the invention stimulation isprovided to control minute ventilation to therapeutically effect bloodgas levels.

In accordance with another aspect of the invention, stimulation isprovided to create a deep inspiration or an increased tidal volume tothereby reduce sympathetic nerve bias, improve blood gas levels,stimulate reflexes for example the Hering-Bruer reflex related toactivating stretch receptors, increase lung volume, normalize or resetbreathing or provide other beneficial therapies to improvecardiovascular function or heart failure condition.

In accordance with another aspect of the invention stimulation may beprovided to modulate intrathoracic pressure to thereby produce atherapeutic effect. Modulation of intrathoracic pressure is expected toimpact sympathetic activation and improve heart conditions. It is knownthat in chronic heart failure settings, increased cardiac fillingpressures and/or pulmonary pressures may cause a direct or indirectreflex increase in sympathetic efferent outflow to the heart. Therefore,a sustained reduction or average reduction in intrathoracic pressurethrough modulation of intrathoracic pressure could have an oppositeeffect and reduce sympathetic efferent outflow to the heart. One wouldexpect to reduce norepinephrine spillover through intrathoracic pressuremodulation which is beneficial to the heart failure patient. Parker etal. used a lower body pressure chamber to show certain reduction in bodypressure leads to reduction in cardiac filling pressures leading toreduction in norepinephrine spillover in acute setting. Longer termapplication this therapy has potential to improve the heart failure andalso remodel the cardiac tissue.

The devices and methods described may achieve similar results throughvarious modes of phrenic nerve and/or diaphragm stimulation. Thesestimulation modalities include low-level stimulation overlapped withpatient intrinsic breathing, diaphragm bias, breath augmentation,increase in tidal volume, increase in inspiration duration, deepinspiration, breathing entrainment, manipulation of exhalation periodand volume, increasing and maintain resting lung volume or functionalresidual capacity, sustained stimulation during inspiration and/orexhalation, continuous stimulation, stimulation synchronized withrespiratory cycles, or cardiac cycles, and/or duty-cycled typestimulation based on a percentage of time, for example, 20% of the timeduring the day or night and when patient is sleep or awake. Theduty-cycled type stimulation could be synchronized to a respiratorycycle or not.

In accordance with another aspect of the invention, stimulation may beprovided to modulate intrathoracic pressure targeting a sustainedreduction in average central venous pressure to effectively reduce rightarterial and right ventricular pressures and pulmonary wedge pressure.Reduction in right ventricular pressure in heart failure patients leadsto increase stroke volume and therefore cardiac output. The sustainedincrease in cardiac output though reduction in filling pressure willlead to reductions in pulmonary congestion which is a major reason foracute heart failure decompensation and therefore hospitalization. Someother hemodynamic effects of this stimulation could be reduction inheart rate as results of increased in cardiac output and/or reduction infilling pressures.

In accordance with another aspect of the invention, stimulation may beprovided to modulate intrathoracic pressure targeting a sustained orincremental reduction in renal pressure or the average renal pressure toimprove kidney function and filtration. Abnormal renal function iscommon in acute and chronic heart failure. It is expected a change inblood volume, cardiac filling pressures, central venous pressure, atrialor ventricular pressures, cardiac output, and/or hemodynamicsintervention could lead to improvement of renal function. Intrathoracicpressure modulation could have an impact on pressure within inferior andsuperior vena cava as well as central venous pressures. Activation ofrenal sympathetic activity through modulation and manipulation of thesepressures could have an impact on kidney pressure and blood transferrate and ultimately kidney glomerular filtration rate (GFR) and leadingto reduction in kidney failure as well as reducing congestion or bloodbacking up into the lungs through increased filtration. Any of thementioned phrenic nerve or diaphragm stimulation modalities included inthis application could be applied at various situations depending on theneed of the patient and sensed parameters. Literature has shown thatelevated cardiac filling pressures are associated with reduced GFR.Therefore the present invention tries to reduce cardiac filling pressurethrough phrenic nerve stimulation and to increase GFR.

In accordance with another aspect of the invention, intrathoracicpressure modulation could be used to treat patients with pulmonaryhypertension. Pulmonary hypertension is result of increased pulmonarypressures. Reduction or modulation of intrathoracic pressure could leadto reduction or treatment of pulmonary hypertension.

In accordance with another aspect of the invention the stimulation couldbe activated by the patient using an external device. The stimulationcould be also activated by sensing increased physical activity throughan activity sensor or increased in heart rate or respiration rate orother mechanism indicating need for supplemental cardiac output orreduction in filling pressures. For example, a thoracic or lungsimpedance sensor or a list of sensors including in the referencedpublication cold be used to activate stimulation to deliver therapy toimprove hemodynamics.

In accordance with another aspect of the invention stimulation isprovided to reduce breathing disorders to thereby improve condition of aheart failure patient.

In accordance with another aspect of the invention a combined cardiacrhythm management device including leadless devices anddiaphragm/phrenic nerve stimulation device is provided to provide anenhanced combined treatment device.

In accordance with another aspect of the invention, leadless phrenicnerve electrodes could be injected, delivered, or placed in the vicinityof the phrenic nerve and stimulation cold be performed through anexternal or integral pulse generator. The sensor or sensors tosynchronize the stimulation could be also internal or external to thebody.

In accordance with another aspect of the invention a combined vagalnerve, hypoglossal nerve, or cardiac plexus stimulation managementdevice and diaphragm/phrenic nerve stimulation device is provided toprovide an enhanced combined treatment device.

The system may also be utilized to provide a continuous or synchronizedlow level stimulation to the phrenic nerve or diaphragm overlapped withthe patient's own intrinsic breathing to reduce an intrathoracicpressure and improve cardiac output. The patient's SaO2 levels may alsobe improved and the heart and respiration rates may be reduced.

Various mapping and/or neurostimulating electrodes may be utilized withthe methods and devices described herein. For instance, such mappingand/or neurostimulating electrodes may be employed in conjunction with acardiac pacemaking or defibrillation lead and more particularly amapping and neurostimulation electrodes employed over the cardiacpacemaking or defibrillation lead while the cardiac lead is either invivo and resident within the vascular structure. These electrodes may beplaced simultaneously with neurostimulation electrodes or leads. Themapping and neurostimulation electrodes used in conjunction with thecardiac pacemaking or defibrillation lead herein is referred to as themapping and neurostimulation electrodes.

The mapping and neurostimulation electrodes may be employed inconjunction with a cardiac lead and for interventional therapy such asneurostimulation to patients who have already had a cardiac leadinstalled.

Such electrodes also overcome many of the problems that exist withconventional cardiac leads or cardiac leads with integralneurostimulation electrodes. If a patient has been implanted with anexisting, conventional cardiac lead and that same patient requiresadditional interventional neurostimulation at any point after theexisting cardiac lead has been implanted, the original cardiac lead mustbe explanted and the entire cardiac lead must be replaced. Theelectrodes described herein may be installed over the excising cardiaclead and advanced down the cardiac lead body into a therapeutic positionwithout removing or re-positioning the existing cardiac lead.

In addition, a conventional cardiac lead with integral neurostimulationelectrodes, whether the neurostimulation electrodes are integral to thecardiac lead or whether the neurostimulation electrodes are sutured ontothe cardiac lead, typically must be installed concurrently when thecardiac lead is originally installed into the patient. The relationshipbetween the neurostimulation electrode and the cardiac electrode isfixed prior to implant and therefore positioning for either theneurostimulation electrodes or the cardiac electrode is sub-optimal.

Yet the electrodes described herein are completely independent andmobile and have the ability to be installed over an existing cardiaclead. Moreover, the mapping and neurostimulation electrodes can bepositioned independently of the cardiac electrodes. This independentpositioning ability allows for both mapping and neuro-stimulatingelectrodes as well as the cardiac electrode's positioning to beoptimized.

The temporary or chronic mapping and neurostimulation electrodes couldbe inserted through several approaches including femoral, radial, rightor left Subclavien veins or right or left jugular veins or in othertransvenous approaches placed in veins or arteries overlapping right orleft phrenic nerve. Some electrode systems/catheters could map andstimulate both phrenic nerves through transvenous approaches. In caseswhere there are needs for both phrenic nerves to be stimulatedsimultaneously, with delays, or in sequence, a single electrode/leadssystem or two electrode/leads systems could be deployed.

Lastly, a conventional cardiac lead with integral neurostimulationelectrodes or neurostimulation electrodes sutured onto the cardiac leadbody are iso-diametric and are aligned randomly. The random alignmentcould limit therapy because the electrical field if not focused towardsthe neural anatomy as the electrodes will not energize the nerve. Theelectrodes described herein are designed to deploy the neurostimulationelectrodes and bias the neurostimulation electrode towards the vesselwall and in a position that is tangent to the neural anatomy residingoutside the vessel wall. The biased or focused neurostimulationelectrodes assure the electrical field induced by the neurostimulationelectrodes is optimized towards the neural anatomy.

These and other aspects of the invention are set forth herein in theabstract, specification and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a chart illustrating examples of possible beneficial effectsof stimulation in accordance with an aspect of the invention.

FIG. 1B is a pressure volume curve illustrating use of stimulation inaccordance with an aspect of the invention.

FIGS. 2A, 2B and 2C illustrate respectively, flow, tidal volume andstimulation envelope signals corresponding to use of a device and methodin accordance with an aspect of the invention.

FIGS. 3A, 3B, 3C and 3D illustrate respectively, EMG, flow, tidal volumeand stimulation envelope signals corresponding to use of a device andmethod in accordance with an aspect of the invention.

FIGS. 4A, 4B, and 4C illustrate respectively, flow, tidal volume andstimulation envelope signals corresponding to use of a device and methodin accordance with an aspect of the invention.

FIGS. 5A, 5B, and 5C illustrate respectively, flow, tidal volume andstimulation envelope signals corresponding to use of a device and methodin accordance with an aspect of the invention.

FIG. 6 is an isometric view of a mapping electrodes mounted on a mobilesleeve which is descending over a cardiac lead;

FIG. 7 is an isometric view of a mapping electrodes mounted on a mobilesleeve which is descending over a cardiac lead and includes deployedneuro-stimulation electrodes;

FIG. 8 is an enlarged isometric view of mapping electrodes mounted on amobile sleeve including neuro-stimulating electrodes deployed on anexpandable wire member;

FIG. 9A is an exemplary side view of a neuro-stimulation electrodedeployed, e.g., in a subclavian vein.

FIGS. 9B and 9C show detail side views of one mechanism for deployingthe electrodes.

FIG. 10 is a detail side view of a neuro-stimulation electrode.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with one aspect of the invention, stimulation to elicit adiaphragm response is provided to increase or normalize lung volume andin particular to increase functional residual capacity. It is believedthat stimulation to increase or to normalize lung volume or functionalresidual capacity may have one or more effects that may be therapeuticto cardiovascular or heart failure patients.

In accordance with this aspect of the invention stimulation may beprovided using a device or method as described in one or more of therelated patent applications set forth herein, to increase or normalizelung volume or functional residual capacity. For example, a biasstimulation may be provided to increase functional residual capacity orto bias lung volume for a period of time. It is believed that increasingfunctional residual capacity may have one or more therapeutic effectsfor heart failure or other cardiovascular patients, such as, forexample, reducing effort required to breathe; improving gas exchange,improving SaO2 levels; providing a buffer to reduce fluctuations inblood gas levels and to reduce the likelihood of crossing the PCO2apneic threshold; and reducing episodes of obstructive apnea in OSApatients and central sleep apnea episodes. Such buffer may alsostabilize blood gases to counter fluctuations in gas levels caused bycirculatory delay that may lead to Cheyne-Stokes respiration and CentralSleep Apnea. Other stimulation may be provided to achieve improved SaO2levels or gas levels, for example, as set forth in the related patentapplications which are incorporated completely and without limitationherein by reference. Other stimulation may be provided that may have theeffect of normalizing lung volume, including but not limited to lowfrequency stimulation, low energy stimulation, or deep inspirationstimulation. These various stimulation techniques may also be providedor configured to have the effect of increasing SaO2 levels to reduceload on the heart and cardiac filling pressures.

FIG. 1A illustrates stimulation provided with a device or method inaccordance with the invention. Stimulation is provided using a device ormethod for stimulating tissue to elicit a diaphragm response 1000.Stimulation increases or normalizes lung volume or FRC 1001. Theincrease or normalization or lung volume may improve gas exchange;increase SaO2, and/or improve breathing stability 1002. The increase ornormalization of lung volume or FRC may move a patient to a more optimallocation on the volume pressure curve 1003 as described in more detailwith respect to FIG. 1B. Providing stimulation to increase FRC may alsoallow improved gas exchange during pulmonary edema where lung inflationcreates a gradient for liquid movement from alveolar space to theextra-interstitium 1004. It is believed that moving fluids to theinterstitial space will improve ventilation because removal of fluidsfrom the alveolar region will permit improved gas exchange. An increaseor normalization of lung volume or FRC may also treat OSA or CSA inpatients with OSA (obstructive sleep apnea) or CSA (central sleep apnea)and thereby benefit the cardiovascular system 1005. For example, one ormore devices and methods described in copending patent applications setforth above may be used to treat OSA or CSA. Increased or normalizedlung volume, FRC, increased inspiration duration or elongated exhalationperiod all lead to reduction in average, sustained, or instantaneousintrathoracic pressures leading to improved cardiac, pulmonary, andrenal pressures all simultaneously lead to reduction or prevention ofpulmonary congestion.

FIG. 1B illustrates a pressure/volume curve 1010 illustrating arelationship between transthoracic pressure and lung volume. Thisexample illustrates, among other things how stimulation may be providedto reduce breathing effort and/or intrathoracic pressure change for agiven inspiration volume. At lower lung volumes 1011, a greater changein pressure is required to increase lung volume a given amount throughinspiration, thus providing a greater work of breathing and therebyincreasing metabolic requirements and load on heart as well. Similarlyat higher lung volumes 1013, greater change in pressure and effort arerequired to increase lung volume through inspiration. However, inbetween the lower volumes 1011 and higher volumes 1013 there is asteeper portion of the curve 1012 where at a given lung volume,inspiration produces an efficient increase in lung volume with lesschange in pressure required to effect a given volume and therefore lesseffort required by the respiratory muscles to produce a given change inpressure. It is believed that an increase in required effort to breathemay result in poorer breathing or less effort and gas exchange,particularly in heart failure patients. It is also believed that greaterfluctuations in intrathoracic pressure may contribute the conditionsaffecting heart failure. Thus in accordance with one aspect of theinvention, stimulation may be provided to increase resting lung volumeso that greater breathing efficiency and gas exchange is provided. Wherea patient's normal resting lung volume or functional residual capacityis typically low, it may be increased. Where a patient's resting lungvolume is lower than normal for a healthy individual, it may benormalized so that it is brought to a level where efficient breathingoccurs. For example a low lung volume 1014 may be increased to higherlung volumes 1015 or 1016 which are at an efficient volume 1012 on thepressure volume curve 1010.

Stimulation may be provided on a sustained or intermittent basis.Stimulation may be provided when a patient is asleep or awake. Inaccordance with one aspect of the invention, stimulation is provided tocompensate for lung volume lost at the onset of sleep or during sleep.In accordance with one aspect of the invention the stimulator may beturned on by the patient prior to sleeping or may be triggered by asensed parameter or real time clock. A sensor may be used to sense oneor more physiological parameters indicating onset or a specific stage ofsleep. Other sensors may sense one or more conditions that may be usedto determine appropriate times or parameters for stimulation.

In accordance with another aspect of the invention stimulation isprovided to control breathing to reduce respiration rate and therebyimprove, prevent or slow cardiac disease by reducing hypertension,reducing sympathetic nerve activation, providing SaO2 levels, and/orincreasing cardiac output. It is believed that lowering breathing ratewill provide a decrease in cardiac rate, and an enhanced vagal response.

In accordance with one aspect of the invention, breathing rate may becontrolled by augmenting breathing or stimulating during intrinsicbreathing to increase peak tidal volume and/or to increase inspirationduration. Increasing the duration of inspiration or tidal volume it isbelieved will cause the timing of the next intrinsic breath to bedelayed due to the central nervous controller tendency to maintainminute ventilation in absence of any change at the chemoreceptor level.The rate may be continuously slowed by detecting each intrinsic breathand providing stimulation or augmenting until the duration ofinspiration, tidal volume or exhalation rate is at a level that bringsthe breathing rate to a desired rate which is reduced by the centralnervous control of minute ventilation.

FIGS. 2A to 2C illustrate stimulation during intrinsic breathing inaccordance with one aspect of the invention. FIG. 2A illustrates flowfor breaths 201, 202, 203, 204 and 205. FIG. 2B illustrates tidal volumeof breaths 201, 202, 203, 204, and 205. Breaths 201, 202 are intrinsicbreaths. Breaths 203, 204, and 205 are intrinsic breaths that areaugmented by stimulation configured to elicit a diaphragm response asillustrated schematically by stimulation markers 213, 214, and 215.

Stimulation is initiated at a period of time during inspiration and isprovided for a period a time in a manner configured to increase tidalvolume. Stimulation during intrinsic breathing and augmenting breathingare described in one or more related applications as set forth hereinwhich are incorporated completely and without limitation herein byreference. The tidal volume TV2 of the breaths 203, 204, 205 whereinspiration is augmented is greater than the tidal volume TV1 of theintrinsic breaths 201, 202. According to one variation, the peak flowduring stimulation Pf2 may be configured as shown to be close to thepeak flow Pf1 during intrinsic breathing. The inspiration duration TI1of intrinsic breathing is shorter than the inspiration duration TI2 ofaugmented breaths 203, 204, 205. The duration TD1 of intrinsic breathingis increased to duration TD2 and with stimulation signals 213 214, 215,to achieve a desired rate.

In accordance with another aspect of the invention, stimulation duringintrinsic breathing may be provided to inhibit or delay onset of nextinspiration. According to an aspect, stimulation may be provided duringexhalation to inhibit or delay onset of an inspiration thereby slowingbreathing rate. According to an aspect, stimulation may be provided toextend exhalation thereby delaying the onset of a subsequentinspiration. According to an aspect, stimulation may be provided at alow energy, low level or low frequency to inhibit onset of aninspiration, thereby slowing breathing rate. Examples of low energy, lowlevel and/or low frequency stimulation are set forth in the relatedapplications herein.

The rate of intrinsic breathing may be controlled by delaying intrinsicbreaths with low energy (for example a lower amplitude, frequency and/orpulse width than desired for paced breathing) diaphragm stimulationprovided during intrinsic breathing.

According to one aspect, low energy stimulation may be provided duringintrinsic breathing, delaying onset of the next breath and therebyslowing breathing rate. According to another aspect, stimulation may beinitiated sufficiently prior to the onset of the next breath so as toreduce the likelihood that the stimulation would trigger a breath. Acombination of lower energy stimulation and timing the stimulationsufficiently prior to the onset of the next breath may be used to slowbreathing rate.

FIGS. 3A to 3D illustrate stimulation provided to slow breathing inaccordance with one aspect of the invention. FIG. 3A illustratesintrinsic diaphragm EMG activity corresponding to breaths 301 through307. FIGS. 3B and 3C respectively illustrate flow and tidal volumecorresponding to breaths 301 through 307. FIG. 3D illustratesstimulation envelopes corresponding to stimulation signals 313, 314,315, 316, and 317 provided prior to onset of breaths 303, 304, 305, 306,and 307 respectively. Stimulation 313, 314, 315, 316, 317 is providedprior to the onset of breath 303, 304, 305, 306, 307 respectively, asdetermined, for example, by a model that predicts the onset of breathingor by the actual detection of the intrinsic diaphragm EMG activity (FIG.3A). Stimulation is sustained for a period of time. For example, thestimulation may be provided until the onset of the intrinsic breath isdetected by the EMG or other physiological signals. As illustrated, thestimulation increases the duration of a respiration cycle T2 withrespect to the duration T1 of an intrinsic breathing cycle. As furtherillustrated, intrinsic breathing cycles 303 to 307 may have greater flowor tidal volume to compensate for the slower breathing rate that isinduced by the stimulation.

In accordance with another aspect of the invention, stimulation toincrease tidal volume or inspiration duration may be provided incombination with stimulation during exhalation to inhibit or delay theonset of the next inspiration.

In accordance with another aspect of the invention stimulation may beprovided to delay exhalation by stimulating at the end of inspiration ata level that slows exhalation. Such stimulation may be provided bystimulating during intrinsic breathing or by providing paced breathingfor example that maintains minute ventilation while providing a slowerrate of breathing.

FIGS. 4A-4C illustrate stimulation during intrinsic breathing inaccordance with one aspect of the invention. FIG. 4A illustrates flowfor breaths 401, 402, 403, 404 and 405. FIG. 4B illustrates tidal volumeof breaths 401, 402, 403, 404 and 405. Breaths 401, 402 are intrinsicbreaths. Breaths 403, 404, and 405 are intrinsic breaths that areaugmented by stimulation configured to elicit a diaphragm response asillustrated schematically by stimulation markers 413, 414, and 415.Stimulation is initiated at a period of time at the end of inspirationand is provided for a period a time through the exhalation period.Detection and stimulation techniques are set forth, for example inrelated applications hereto. Stimulation may be provided at a low energylevel including at a low frequency. Stimulation during intrinsicbreathing and augmenting breathing, low level and/or low frequency aredescribed in one or more related applications as set forth herein whichare incorporated completely and without limitation herein by reference.The peak flow during stimulation Pfb may be greater than the peak flowPfa during intrinsic breaths 401, 402 as illustrated. The peak flowduring stimulation Pfb may be also not be greater than the peak flow Pfaduring intrinsic breaths 401, 402. Similarly tidal volume Tb is forbreaths 404, 405 after stimulation 413 and 414 respectively. Suchgreater flow or tidal volume may intrinsically compensate for the slowerbreathing rate that is induced by the stimulation. It is believed thatstimulation during exhalation inhibits or delays onset of inspiration.The stimulation also slows exhalation (i.e., during the period whichexhalation is occurring at a relatively faster rate) so that theexhalation duration TEb during stimulation is greater than the intrinsicexhalation duration TEa. Exhalation is slowed by stimulation thusslowing the overall rate of breathing. The duration of the intrinsicbreathing respiration cycle TDa is increased to duration TDb duringstimulation, thus reducing the breathing rate to a desired rate.

Stimulation may also be provided to slow or control breathing rate in amanner that provides a paced breath with controlled exhalation asillustrated for example in U.S. Pat. Nos. 8,412,331 and 8,200,336.

FIGS. 5A to 5C illustrate stimulation used to control breathing andbreathing rate in accordance with the invention. Breaths 501 and 502 areintrinsic breaths occurring at a rate such that the duration of therespiration cycle is TDi and having tidal volume TVi and peak flow PFi.Breaths 503, 504 and 505 are paced breaths with higher tidal volume TVpand peak flow PFp. Peak flow PFp may be controlled to be at a levelsubstantially the same as, higher, or lower than intrinsic peak flow.Paced breathing is provided in a manner in which breathing is controlledor taken over by stimulated breathing. Examples of techniques forcontrolling breathing, respiratory drive and/or taking over breathingare set forth in related applications incorporated completely andwithout limitation herein by reference. In general greater tidal volumepermits a reduction in breathing rate or an increase in duration ofbreathing cycle to TDii while maintaining minute ventilation. FIG. 5Cillustrates stimulation envelopes 513, 514, 515 respectivelycorresponding to stimulated breaths 503, 504, 505.

In accordance with another aspect of the invention stimulation isprovided to control minute ventilation to therapeutically affect bloodgas levels. Examples of controlling minute ventilation are set forth forexample in U.S. Pat. No. 8,412,331. Such stimulation may be provided,for example, during sleep to thereby increase or normalize SaO2 levelsduring sleep. In accordance with one aspect of the invention minuteventilation is controlled to normalize SaO2 levels while not decreasingPaCO2 levels close to the apneic threshold. According to this aspectminute ventilation may be actively controlled using sensors to senseSaO2 or PaCO2 levels. Weaning off of pacing may be desirable to insurethat the intrinsic drive to breath is still present. Paced breathing maybe calibrated, for example at implant or adjusted during device use, sothat the device is able to provide the appropriate minute ventilation ateach pacing setting. This information may be obtained for examplethrough sleep studies where the device is designed to providestimulation during sleep.

In accordance with another aspect of the invention, stimulation isprovided to create a deep inspiration or an increased tidal volume tothereby reduce sympathetic nerve bias, improve blood gas levels,stimulate reflexes (for example the Hering-Bruer reflex related toactivating stretch receptors), increase lung volume, normalize or resetbreathing (one or more parameters) or provide other beneficial therapiesto improve cardiovascular function or heart failure condition.

Examples of creating deep inspiration are set forth in US PatentApplication Publication No. 2006/0167523. While these examples refer tousing deep inspiration to treat apnea, similar techniques forstimulation may be used to create deep inspiration breaths for improvingcardiovascular function or treating heart failure. Stimulation may beprovided during intrinsic inspiration or in between inspiration cycles.

In accordance with another aspect of the invention stimulation may beprovided to manipulate intrathoracic pressure to thereby produce atherapeutic effect.

According to one embodiment, stimulation is provided to reduceintrathoracic pressure through induced contraction of the right and/orleft hemidiaphragm. It is believed that for some patients, reduction inintrathoracic pressure may have a beneficial effect on the patient'scardiovascular function or condition. For example, a reducedintrathoracic pressure may increase stroke volume at least in partthrough a decrease in central venous pressure; and reduce pulmonaryarterial and wedge pressures in relation to atmospheric. A reducedintrathoracic pressure may also provide a decrease in filling pressurein the right ventricle and may also thereby improve systemic venousreturn. A reduced intrathoracic pressure may also provide bettercoronary artery perfusion.

In accordance with one aspect of the invention, patients with heartfailure manifesting in poor ventricular filling may be treated withstimulation to reduce intrathoracic pressure. In accordance with oneaspect of the invention, patients with diastolic heart failure may betreated with stimulation to reduce intrathoracic pressure. In accordancewith another aspect of the invention stimulation to reduce intrathoracicpressure may be provided to patients who are hypovolemic where thetherapeutic effects of improved ventricular filling and venous returnwould be particularly beneficial.

According one aspect of the invention stimulation is provided to elicita diaphragm response to cause a reduced intrathoracic pressure. Thestimulation is provided at a level that does not elicit a breath, inother words, where intrinsic breathing continues to occur. Examples ofstimulation such as bias stimulation and low energy or low frequencystimulation are described in related applications set forth herein. Thestimulation eliciting a reduced intrathoracic pressure may be sustainedor intermittent. Stimulation is preferably provided when a patient issleeping but may also be provided when a patient is awake.

In accordance with one aspect of the invention, stimulation may beprovided to one hemidiaphragm to elicit a more impactful change inintrathoracic pressure in the respective side of the thoracic cavity.For example the right hemidiaphragm may be stimulated in such a way tocause a reduced intrathoracic pressure primarily in the right thoraciccavity to thereby effect the right side of the heart to a greater degreethan the left. Or stimulating unilaterally on the diaphragm may serve tominimize the pressure changes that the heart is exposed to. This may bebeneficial when an increased lung volume is desired to treat OSA or CSA.Sensors may be used to sense arterial and venous blood volume so thatstimulation may be adjusted based on patient's blood volume state. Forexample, stimulation may be increased or turned on when the patient isin a hypovolemic state where in a particular patient a greater benefitwould be produced with a more negative intrathoracic pressure. Suchsensors may include, for example, impedance (plethysmography) sensorsused to monitor fluid levels in the body. Separate electrodes, orexisting stimulation electrodes may be used in a configuration or withfrequencies that can determine resistance and/or reactance. Fluid volumechanges may, for example, be monitored based on a baseline establishedwith the sensors and a hyper or hypo volemic state may be detected. Alist of possible sensors are described in the references above.

In accordance with another aspect of the invention, stimulation isprovided to elicit a diaphragm response that improves heart failure asdescribed above in combination with treating sleep disorders thatcontribute to or worsen heart failure. Accordingly, stimulation isprovided as described in the related patent applications set forthherein, to elicit a diaphragm response to thereby reduce breathingdisorders to thereby improve condition of a heart failure patient. Oneor more specific methods of reducing sleep disordered breathing eventsand preventing sleep disordered breathing are described in relatedapplications as set forth herein. In accordance with one aspect of theinvention, stimulation is provided prior to a physiological trigger of acentral or obstructive sleep apnea event in a manner that reduces theoccurrence of such events, thus reducing the effects of apnea eventsthat worsen heart failure.

In accordance with another aspect of the invention a combined cardiacrhythm management device and diaphragm/phrenic nerve stimulation deviceis provided to provide an enhanced combined treatment device. Inaccordance with this aspect of the invention, the diaphragm stimulationelement may comprise an abdominally placed stimulator positioned on thediaphragm or phrenic nerve, a thoracoscopically placed stimulatorpositioned on the diaphragm or phrenic nerve, a phrenic nerve stimulatorpositioned in the neck region on or adjacent the phrenic nerve(transcutaneous, percutaneous, or otherwise implanted); transcutaneousstimulation of the diaphragm through leads at or near the ziphoid region(this may be in combination with a defibrillator function or device thatis configured for subcutaneous stimulation of the heart); or apectorally positioned lead, for example, placed transvenously in a veinor artery in proximity of one or both phrenic nerves.

The system may be further enhanced through the ability to avoid negativedevice/device interactions where a separate controller is used, e.g. fora CRT, pacemaker, ICD or other therapeutic electrical stimulationdevice. The system may also provide arrhythmia and sleep disorderdetection algorithms through sensing of both the cardiac and respirationcycles.

The system may also be included in a combination with a CRM devicehaving a common controller.

Additionally, the system may also be utilized to provide a continuous orsynchronized low level stimulation to the phrenic nerve or diaphragmoverlapped with the patient's own intrinsic breathing to reduce anintrathoracic pressure and improve cardiac output. The patient's SaO2levels may also be improved and the heart and respiration rates may bereduced.

This may be achieved in part by sensing and/or monitoring the patient'sintrathoracic pressure levels and applying the continuous orsynchronized stimulation, as described herein, to reduce or alleviatethe patient's elevated intrathoracic pressure. In applying thestimulation to the patient's phrenic nerve or diaphragm, any of thesensing and stimulation devices and methods described in the followingmay be utilized for applying the continuous or synchronized low levelstimulation: U.S. Patent Application Ser. No. 61/893,404 filed Oct. 21,2013; 60/925,024 filed Apr. 18, 2007; Ser. No. 13/598,284 filed Aug. 29,2012 (US Patent Application Publication No. 2012/0323293); Ser. No.12/082,057 filed Apr. 8, 2008 (now U.S. Pat. No. 8,265,759); Ser. No.12/069,823 filed Feb. 13, 2008 (US Patent Application Publication No.2008/0215106); Ser. No. 12/044,932 filed Dec. 21, 2007 (now U.S. Pat.No. 8,369,398); Ser. No. 11/981,342 filed Oct. 31, 2007 (now U.S. Pat.No. 8,140,164); Ser. No. 11/480,074 filed Jun. 29, 2006 (now U.S. Pat.No. 8,160,711); Ser. No. 11/271,315 filed Nov. 10, 2005 (now U.S. Pat.No. 8,244,358); Ser. No. 11/271,554 filed Nov. 10, 2005 (now U.S. Pat.No. 9,259,573); Ser. No. 11/271,353 filed Nov. 10, 2005; Ser. No.11/271,264 filed Nov. 10, 2005 (now U.S. Pat. No. 7,979,128); Ser. No.11/271,726 filed Nov. 10, 2005 (now U.S. Pat. No. 7,970,475); Ser. No.10/966,487 filed Oct. 15, 2004 (US Patent Application Publication No.2005/0085734); Ser. No. 10/966,484 filed Oct. 15, 2004 (US PatentApplication Publication No. 2005/0085869); Ser. No. 10/966,421 filedOct. 15, 2004 (now U.S. Pat. No. 8,412,331; 10/966,472 filed Oct. 15,2004 (now U.S. Pat. No. 8,200,336); Ser. No. 10/686,891 filed Oct. 15,2003 (now U.S. Pat. No. 8,467,876). Each of these applications isincorporated completely and without limitation herein by reference forany purpose.

Recent sensors and blood pressure and impedance sensing technologieshave proven detecting worsening of heart failure as discussed in theAppendix below. The Appendix is incorporated herein by reference in itsentirety for any purpose. A majority of these sensors monitor bloodpressures within the pulmonary artery, right ventricle, left atrium,intrathoracic, or utilizing ventricular contractions or thoracicimpedance to measure and monitor changes that could lead to hearthemodynamics decompensation or worsening and eventually hospitalization.These devices generally transmit a wireless signal through the sensor ora device that they are attached to the patient or caregiver forintervention that incudes medication therapy or lifestyle or physicianvisit. However, none of these sensor technologies have offered areal-time therapy within the implantable device to improve cardiacoutput and also reduce intrathoracic, pulmonary, or cardiac pressures.

As described in the Appendix and herein, the implantable devices alsoinclude at least one phrenic nerve or diaphragm stimulation lead orelectrodes to deliver therapy either reactively (in response to sensorsand programmed parameters outcome) or proactively as determined dutycycle of a patient-induced event. Upon detection of an increase inpressures, the device may deliver stimulation in such a manner to reduceintrathoracic pressure and related pulmonary and cardiac pressures. Suchtherapy is expected to reduce pulmonary congestion and dyspnea in heartfailure patients.

Another application of this device/technology is to improve cardiachemodynamics by increasing venous return and cardiac output.

Another application of this technology includes applying negativepressure therapy even in the absence of increased pressures and toimprove cardiac output and off-loading the heart. In the long-term, theheart could remodel and improve contractility on its own.

The implantable sensor could receive energy from outside the body suchas the CardioMEMS pulmonary pressure sensor and then receive commands tostimulation phrenic nerve to reduce pressures and increase cardiacoutput. The stimulation electrodes could be also activated from outsidethe body.

Another application of this device is treating central and obstructivesleep apnea as described in further detail in the patent applicationsincorporated hereinabove.

Such devices could also synchronize its stimulation of the phrenic nerveto cardiac cycles such systole or diastole. However, in order to achievesustained reduction in pulmonary or atrial pressures, a sustainedstimulation that is synchronized to respiration cycles and also cardiaccycles may be provided. Intrathoracic pressure is lowest at the peak ofinspiration and therefore while it is possible to stimulate, thestimulation applied toward the end of inspiration and/or part of or theentire exhalation phase may be more efficient.

The stimulation algorithm could be targeted toward multiplebenefits/targets. At the time of device implant, the algorithms for eachtarget could be titrated and thresholds could be established perpatient:

-   -   1. Proactive stimulation during sleep or awake to increase        cardiac output in diastolic or systolic heart failure patients;        -   a. Device will self-adjust stimulation relative to the need            for certain cardiac output increase;    -   2. Responsive therapy where the device monitors pressures or        cardiac and intrathoracic impedances or cardiac output and        therefore responds to need to reduce intrathoracic pressure;    -   3. Responsive device to increase cardiac output;    -   4. Responsive device to increase lung volume;    -   5. Integrated with any CRM device; pacemaker, defibrillator,        cardiac resynchronization therapy (CRT);    -   6. Integrated with other heart failure devices such as vagal        nerve stimulation or others;    -   7. Integrated with sleep apnea therapy devices including        hypoglossal nerve stimulation devices.    -   8. Responsive therapy device to improve kidney function or        improve GFR    -   9. Responsive device to reduce pulmonary pressures and pulmonary        congestions

In one example, because the algorithms for each target are able to betitrated, the phrenic nerve or diaphragm tissue may be stimulated tocause a titratable diaphragm contraction such that an initial pressurewithin a thoracic chamber is reduced. In another example, the phrenicnerve or diaphragm tissue may be stimulated to improve a cardiac outputin titratable manner as well.

In stimulating the phrenic nerve or diaphragm as well as monitoring thepatient's intrathoracic pressure, as described herein, the electrodesmay be utilized in combination with or integral to a cardiac lead. Suchelectrodes are described in further detail in U.S. Patent ApplicationSer. No. 61/893,404 filed Oct. 21, 2013, which has been incorporated byreference hereinabove in its entirety and for any purpose.

The mapping and neurostimulation electrodes presented herein areintended to be used in conjunction with or integral to a cardiac lead.They could also be an independent lead. The mapping electrodes mountedon the sleeve is intended to traverse the cardiac lead, providespecificity to specific neural activation points within the vascularstructure where neural anatomy resides adjacent to the vascularstructure, such as the phrenic or vagus nerve. Once the targeted nerveanatomy is identified by the mapping electrodes, the neurostimulationelectrodes can be arranged or deployed within the vascular structure andadjacent to the neural anatomy such that the electrodes provides thedesired neurostimulation therapy.

FIG. 6 illustrates an embodiment of a mapping sleeve 601 that includesat minimum one but in this embodiment plural mapping electrodes 602,traversing a cardiac lead 600. The mapping sleeve 601 in this embodimentis inserted over the cardiac lead 600 at the proximal end of the leadand advanced along the cardiac lead body to a position in which themapping electrodes 602 are arranged to activate neural anatomy.

The mapping sleeve 601 may be constructed of a bio-stable polymer,silicone rubber, or other insulation materials suitable for isolating aplurality of electrodes. The mapping electrodes 602 may be constructedof platinum or platinum alloys but in other embodiments constructed ofany bio-stable conductor, titanium, palladium, stainless steel, carbon,or similar materials, alloys. or composite materials.

Once the neural anatomy is identified within the vascular structure, themapping sleeve 601 is retracted as illustrated in FIG. 7 exposing aninner sleeve 605 that includes an expanding wire member 606. The wiremember may be constructed of any bio-stable compliant metal, nitinol,stainless steel, titanium alloys, or plastic material suitable to expandinto position.

As illustrated in FIG. 8, the expanding wire member 606 in which carriesat least one but in the preferred embodiment, plural neuro stimulatingelectrodes 607. The expanding wire member 606 when in the un-deployedstate, resides under the mapping sleeve so that the entire assembly cannegotiate the vascular structure. The wire 606 may be retained in itslow-profile configuration through various mechanism, such as a stylet608 which may be passed through one or more retaining loops 609 definedalong the wire 606, as shown in the detail view of FIG. 9B. Whendeployed, the stylet 608 may be retracted such that the expanding wiremember 606 expands, as shown in the detail view of FIG. 9C, to apply theneurostimulation electrodes 607 against the vascular wall, as shown inFIG. 9A. In this example, the lead 600 may utilize a IS-1 typeconnector.

FIG. 10 illustrates an embodiment of the deployed neurostimulationelectrodes 607 expanded to reside coincident to the vessel wall 613. Inthe primary embodiment, the electrode wire 606 containing theneurostimulation electrodes 607 have expanded to focus the electrodes607 current towards the neural anatomy residing outside the vascularstructure. In this variation, the electrode wire 606 and electrodes 607may be attached or coupled to a conductor cable 610. A push sleeve 611may be slidingly positioned proximally or distally of the electrode 607with a proximal end of the push sleeve 611 being coupled to a push rod612. During lead insertion and intravascular delivery, the pushingsleeve 611 may remain over the wire 606 and electrodes 607. When theelectrodes 607 are in position relative to the tissue wall, the push rod612 may be actuated proximally or distally relative to the lead 600 suchthat the push sleeve 611 is moved to expose the wire 606 and electrodes607 which may then be deployed as the sleeve 611 is, e.g., retracted.

The mapping electrode may be advanced down a previously implantedcardiac lead body to a point in which neural structure intersects thevascular structure. The mapping electrode is used to identity “map” theoptimal stimulation location or optimal location to place theneurostimulation electrodes within the vascular structure.

Once the optimal stimulation location is identified using the mappingelectrodes, the neurostimulation electrodes are deployed such that theneurostimulation electrodes are positioned in a location to energize thetargeted neural anatomy.

A method of mapping or identifying the nerve is developed where once theelectrode is near proximity of the nerve, stimulations of variety offrequencies and amplitude will be applied in certain sequence foroptimum nerve location. The physiological response to mapping procedurewill be monitored and recorded. Once the electrode is in optimumlocation, the electrode location in reference to other anatomicallandmarks are noted and the electrode is secured. In case of mapping thephrenic nerve, several physiological parameters including diaphragmmovement and response, flow, tidal volume, lung volume, minuteventilation, upper airway muscle activity, and similar parameters as itrelates to respiratory parameters will be monitored in order to identifythe optimum electrode placement in reference to the phrenic nerve.

As a person skilled in the art will recognize from the previous detaileddescription and figures that modifications and changes may be made tothe preferred embodiments of the invention without departing from thescope of this invention defined in the following claims.

We claim:
 1. A method for treating respiratory disorders, comprising:sensing at least one characteristic of a subject's intrinsic respirationvia one or multiple sensors positioned internally or externally relativeto the subject; sensing at least one characteristic indicative of thesubject's intrathoracic pressure; and stimulating a phrenic nerve of thesubject via an electrode positioned in proximity to the phrenic nerve atleast during a portion of the subject's exhalation and/or the subject'srest cycle to maintain a contraction of the subject's diaphragm relativeto a non-stimulated condition during the subject's exhalation and/or thesubject's rest cycle over a sustained period of time via the electrodeto increase a functional residual capacity of the subject's lungs untilthe subject's mean or average intrathoracic pressure is decreased. 2.The method of claim 1, wherein the sensed characteristic of thesubject's intrinsic respiration includes the subject's respiratoryphase, and wherein the phrenic nerve is stimulated during the portion ofthe subject's exhalation and/or the subject's rest cycle such that atleast one breath is augmented to further increase the functionalresidual capacity of the subject's lungs.
 3. The method of claim 1,further comprising monitoring the subject's cardiac output by monitoringa signal indicative of one or more of a pulmonary artery pressure, rightventricle pressure, left atrium pressure, left ventricle pressure,cardiac contractility, and/or cardiac and intrathoracic impedances. 4.The method of claim 1 wherein the stimulation applied to the phrenicnerve is adjusted in response to the at least one characteristic of asubject's intrinsic respiration and/or sensing at least onecharacteristic indicative of the subject's intrathoracic pressure suchthat an initial pressure within a thoracic chamber is reduced.
 5. Themethod of claim 1, wherein the stimulating of the phrenic nervecomprises stimulating to improve a hemodynamic parameter of the heart.6. The method of claim 1, wherein the stimulation applied to the phrenicnerve is adjusted in response to the at least one characteristic of asubject's intrinsic respiration and/or sensing at least onecharacteristic indicative of the subject's intrathoracic pressure toimprove a cardiac output.
 7. The method of claim 1, wherein thestimulating of the phrenic nerve comprises stimulating in an acute orchronic setting.
 8. The method of claim 1, wherein the stimulating ofthe phrenic nerve comprises decreasing a right atrial pressure andimproving kidney filtration.
 9. The method of claim 1, wherein thestimulating of the phrenic nerve comprises reducing a cardiac fillingpressure to reduce the subject's renal pressure.
 10. The method of claim1, wherein the stimulating of the phrenic nerve comprises modulating ormanipulating the intrathoracic pressure to activate renal sympatheticactivity.
 11. The method of claim 1, wherein the stimulating of thephrenic nerve comprises modulating or manipulating the intrathoracicpressure to activate renal sympathetic activity such that a kidneyglomerular filtration rate (GFR) is increased.
 12. The method of claim1, wherein stimulating the phrenic nerve comprises reducing asympathetic efferent outflow to a heart of the patient such thatnorepinephrine spillover is reduced.
 13. The method of claim 1, furthercomprising reducing a renal pressure by decreasing the mean or averageintrathoracic pressure to adjust one or more hemodynamic parameters ofthe subject's heart.
 14. The method of claim 1, further comprisingfurther stimulating the phrenic nerve until a sleep disordered breathingor an episode of sleep apnea is reduced in the patient.
 15. The methodof claim 1, wherein the electrode is positioned within a subclavianvessel.
 16. The method of claim 15, wherein said stimulating stepcomprises positioning the electrode over a cardiac lead within thesubclavian vessel.
 17. A device for treating respiratory disorders,comprising: at least one electrode configured to be positioned inproximity to a phrenic nerve within a patient's body such that the atleast one electrode is in electrical communication with the phrenicnerve; and a control unit in electrical communication with the at leastone electrode, wherein the control unit is programmed to generate anddeliver an electrical stimulation signal through the at least oneelectrode during at least a portion of the subject's exhalation and/orthe subject's rest cycle to maintain a contraction of the subject'sdiaphragm relative to a non-stimulated condition during the subject'sexhalation and/or the subject's rest cycle over a sustained period oftime to increase a functional residual capacity of the patientundergoing intrinsic respiration, and wherein the control unit isfurther programmed to deliver the electrical stimulation signal until amean or average intrathoracic pressure, as determined by the controlunit, is decreased.
 18. The device of claim 17, wherein the control unitis further programmed to stimulate the phrenic nerve during theexhalation and/or rest cycle until at least one breath is augmented tofurther increase the functional residual capacity of the subject. 19.The device of claim 17, further comprising a cardiac lead upon which theat least one electrode is positionable.
 20. The device of claim 17,wherein the control unit comprises a sensor configured to sense acardiac related parameter of the patient.
 21. The device of claim 17,wherein the control unit is programmed to deliver the electricalstimulation signal to cause a diaphragm contraction such that an initialpressure within a thoracic chamber is reduced.
 22. The device of claim17, wherein the control unit is programmed to deliver the electricalstimulation signal to adjust a hemodynamic parameter of the subject'sheart.
 23. The device of claim 17, wherein the control unit isprogrammed to adjust the electrical stimulation signal in response tothe physiologic parameter to improve a cardiac output.
 24. The device ofclaim 17, wherein the control unit is programmed to deliver theelectrical stimulation signal to decrease a right atrial pressure andimprove kidney filtration.
 25. The device of claim 17, wherein thecontrol unit is programmed to deliver the electrical stimulation signalto reduce a cardiac filling pressure to reduce the renal pressure. 26.The device of claim 17, wherein the control unit is programmed todeliver the electrical stimulation signal to modulate or manipulate theintrathoracic pressure to activate renal sympathetic activity.
 27. Thedevice of claim 17, wherein the control unit is programmed to deliverthe electrical stimulation signal to modulate or manipulate theintrathoracic pressure to activate renal sympathetic activity such thata kidney glomerular filtration rate (GFR) is increased.
 28. The deviceof claim 17, wherein the control unit is programmed to deliver theelectrical stimulation signal to reduce a sympathetic efferent outflowto a heart of the patient such that norepinephrine spillover is reduced.29. The device of claim 17, wherein the control unit is furtherprogrammed to deliver the electrical stimulation signal until a sleepdisordered breathing or an episode of sleep apnea is reduced in thepatient body.
 30. The device of claim 17, wherein the at least oneelectrode configured to be positioned intravascularly within asubclavian vessel.